期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2021093118
关键词
Paxbp1; muscle satellite cells; quiescence; ROS; cell growth
资金
- Hong Kong Research Grant Council [GRF16101517, C6018-19G, AoE/M-09/12, AoE/M-604/16, T13-605/18-W]
- Center for Systems Biology Human Health
- State Key Laboratory of Molecular Neuroscience at the Hong Kong University of Science and Technology
- Shenzhen Bay Laboratory (Guangdong, China) [S201101002]
- Hong Kong Epigenome Project
Paxbp1 is a key regulator controlling the transition of MuSCs from quiescence to cycling state, affecting the critical process of cell cycle reentry as well as cell growth and apoptosis. Partial rescue of the cell-cycle reentry defect caused by Paxbp1 deletion can be achieved by reducing ROS levels.
Adult mouse muscle satellite cells (MuSCs) are quiescent in uninjured muscles. Upon muscle injury, MuSCs exit quiescence, reenter the cell cycle to proliferate and self-renew, and then differentiate and fuse to drive muscle regeneration. However, it remains poorly understood how MuSCs transition from quiescence to the cycling state. Here, we report that Pax3 and Pax7 binding protein 1 (Paxbp1) controls a key checkpoint during this critical transition. Deletion of Paxbp1 in adult MuSCs prevented them from reentering the cell cycle upon injury, resulting in a total regeneration failure. Mechanistically, we found an abnormal elevation of reactive oxygen species (ROS) in Paxbp1-null MuSCs, which induced p53 activation and impaired mTORC1 signaling, leading to defective cell growth, apoptosis, and failure in S-phase reentry. Deliberate ROS reduction partially rescued the cell-cycle reentry defect in mutant MuSCs. Our study reveals that Paxbp1 regulates a late cell-growth checkpoint essential for quiescent MuSCs to reenter the cell cycle upon activation.
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